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Off-target (side effects) drug effects identified by computational techniques and confirmed by experimental methods

Recent research from the research group of Professor Mark Distefano.

In collaboration with Professor Brian Shoichet at UCSF, the Distefano lab has investigated the off-target inhibition of protein farnesyltransferase (PFTase) by commercial drugs. The results of their work have been submitted to the Journal of Medicinal Chemistry. The inhibition of protein prenylation has been a target for disease intervention for the past two decades. Drugs that block PFTase have been evaluated as chemotherapeutics for some forms of cancer, anti-parasitic agents to treat malaria and chagas disease, and tools to ameliorate the symptoms of Hutchinson-Gilford progeria syndrome. The Shoichet lab created the Similarity Ensemble Approach (SEA) to relate proteins based on the set-wise chemical similarity among their ligands. SEA has previously revealed cross talk between drugs acting primarily on G-protein coupled receptors (GPCRs). In this work, SEA was used to look for potential off-target inhibition of the PFTase by commercially available drugs. Two commercial drugs, Loratadine and Miconazole, were identified as potential ligands for PFTase and subsequently confirmed as such experimentally. Loratadine is known to bind the Histamine H1 receptor while Miconazole is an inhibitor of the enzyme 14-α-demethylase. These results point towards the applicability of SEA for the prediction of not only GPCR-GPCR drug cross talk, but also GPCR-enzyme and enzyme-enzyme drug cross talk.

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